Prodrugs of NH-acidic compounds: ester, carbonate, carbamate and phosphonate derivatives

Abstract

The invention provides a method of sustained delivery of a lactam, imide, amide, sulfonamide, carbamate or urea containing parent drug by administering to a patient an effective amount of a prodrug compound of the invention wherein upon administration to the patient, release of the parent drug from the prodrug is sustained release. Prodrug compounds suitable for use in the methods of the invention are labile conjugates of parent drugs that are derivatized through carbonyl linked prodrug moieties. The prodrug compounds of the invention can be used to treat any condition for which the lactam, imide, amide, sulfonamide, carbamate or urea containing parent drug is useful as a treatment.

What is claimed is: 
     
       1. A compound of Formula XVII, XVIII or XIX: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof;
 wherein R 1  is selected from —C(O)O—CH 2 —OC(O)R 21  or —C(O)NH-CH 2 —OC(O)R 21 , —C(O)O—CH 2 —OC(O)N(R 21 ) 2 , —PO 3 MY, —P(O) 2 (OR 20 )M and —P(O)(OR 20 )(OR 21 );
 wherein each R 20  and R 21  is independently selected from hydrogen, aliphatic, substituted aliphatic, aryl or substituted aryl; 
 
 Y and M are the same or different and each is a monovalent cation; or M and Y together is a divalent cation; 
 F 1  is R 5 -A-Cy 1 —B-D-;
 wherein, A is selected from absent, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, —S—, —O—, —S(O)—, —S(O) 2 —, —S[C(R 30 )(R 31 )] u —, —S(O)[C(R 30 )(R 31 )] u—, —(O)[C(R   30 )(R 31 )] u —, —N(R 30 )—, —N(R 30 )[C(R 31 )(R 32 )] u —, —[C(R 30 )(R 31 )] u —C(O)[C(R 30 )(R 31 )] u —; 
 wherein each u is independently 1, 2, 3, 4, 5, 6 or 7; 
 Cy 1  is absent or an optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; 
 B is absent, or a linker; 
 D is selected from absent, —O—, —NR 33 , —C(R 34 )(R 35 )—, —S—S(O)—S(O) 2 —, —C(O)—; 
 
 each R 5 , R 30 , R 31 , R 32  R 33 , R 34 , and R 35  is independently selected from absent, hydrogen, halogen, —OR 10 , —SR 10 , —NR 10 R 11 —, —C(O)R 10 , optionally substituted aliphatic, optionally substituted aryl or optionally substituted heterocyclyl; 
 wherein each R 10  and R 11  is independently absent, hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl; alternatively two R 10  and R 11  together with the atoms to which they are attached may form an additional optionally substituted, 3, 4, 5, 6 or 7 membered ring; and, 
 each u is independently 1, 2, 3, 4, 5, 6 or 7. 
 
     
     
       2. A compound having the formula XX, XXI or XXII, or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       Wherein R 1  is selected from —C(O)OR 20 , —C(O)R 20 , —C(O)NR 20 R 21 , —PO 3 MY, —P(O) 2 (OR 20 )M and —P(O)(OR 20 )(OR 21 );
 wherein each R 20  and R 21  is independently selected from hydrogen, aliphatic, substituted aliphatic, aryl or substituted aryl; 
 Y and M are the same or different and each is a monovalent cation; or M and Y together is a divalent cation; 
 Cy 2  is an optionally substituted heterocyclic ring; and 
 X 5  is selected from absent, —S—, —O—, —S(O)—, —S(O) 2 —, —N(R 10 )—, —C(O)—, —C(OR 10 )(R 11 )—, —[C(R 10 )(R 11 )] v —,—O[C(R 10 )(R 11 )] v —,—O[C(R 10 )(R 11 )] v O—,—NR 12 [C(R 10 )(R 11 ) v O—, —NR 12 [C(R 10 )(R 11 )] v  S—, —S[C(R 10 )(R 11 )] v —, —C(O)[C(R 10 )(R 11 )] v —, and —C(R 10 )(R 11 )═C(R 10 )(R 11 )—; wherein v is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and, 
 wherein each R 10  and R 11  is independently absent, hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl; alternatively two R 10  and R 11  together with the atoms to which they are attached may form an additional optionally substituted,  3 ,  4 ,  5 ,  6  or  7  membered ring. 
 
     
     
       3. A compound having the Formula XXIV, XXV or XXVI, or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein R 1  is selected from —C(O)RO 20 , —C(O)R 20 , —C(O)NR 20 R 21 , —PO 3 MY, —P(O) 2 (OR 20 )M and —P(O)(OR 20 )(OR 21 ); 
         wherein each R 20  and R 21  is independently selected from hydrogen, aliphatic, substituted aliphatic, aryl or substituted aryl; 
         Y and M are the same or different and each is a monovalent cation; or M and Y together is a divalent cation. 
       
     
     
       4. A compound of  claim 3 , wherein R 1  is selected from
 Table  1  , or a pharmaceutically acceptable salt thereof; 
 
       
         
           
                 
               
                   TABLE 1 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
             
                
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
       5. A compound having the Formula XXVII, XXVIII or XXIX: 
       
         
           
           
               
               
           
         
         wherein R 1  is selected from —C(O)OR 20 , —C(O)R 20 , —C(O)NR 20 R 21 , —PO 3 MY, —P(O) 2 (OR 20 )M and —P(O)(OR 20 )(OR 21 ), or a pharmaceutically acceptable salt thereof. 
       
     
     
       6. A compound of  claim 5 , wherein R 1  is selected from Table  1 , or a pharmaceutically acceptable salt thereof; 
       
         
           
                 
               
                   TABLE 1 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
             
                
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
       7. A compound of  claim 1  having the Formula XXX, XXXI or XXXII: 
       
         
           
           
               
               
           
         
       
       wherein R 1  is selected from —C(O)OR 20 , —C(O)R 20 , —C(O)NR 20 R 21 , —Po 3 MY, —P(O) 2 (OR 20 )M and —P(O)(OR 20 )(OR 21 ), or a pharmaceutically acceptable salt thereof. 
     
     
       8. A compound of  claim 7 , wherein R 1  is selected from Table  1 , or a pharmaceutically acceptable salt thereof; 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       9. A compound of  claim 1 , wherein said R 1  is —C(O)O—CH 2 —OC(O)R 21 ;
 wherein each R 20  and R 21  is independently selected from hydrogen, aliphatic, substituted aliphatic, aryl and substituted aryl. 
 
     
     
       10. A compound of  claim 1 , wherein said R 1  is —C(O)NH—CH 2 —OC(O)R 21 ;
 wherein each R 20  and R 21  is independently selected from hydrogen, aliphatic, substituted aliphatic, aryl and substituted aryl. 
 
     
     
       11. A compound of  claim 1 , wherein said R 1  is —C(O)O—CH 2 —OC(O)N(R 21 ) 2 ;
 wherein each R 20  and R 21  is independently selected from hydrogen, aliphatic, substituted aliphatic, aryl and substituted aryl. 
 
     
     
       12. A compound of Table H or a pharmaceutically acceptable salt thereof: 
       
         
           
                 
                 
               
                   TABLE H 
                 
                     
                 
                   No. 
                   Structure 
                 
                     
                 
                   1000. 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   1001. 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   1002. 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   1003. 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   1004. 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   1005. 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   1006. 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   1007. 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   1008. 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   1009. 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   1010. 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   1011. 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   1012. 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   1013. 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   1014. 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   1015. 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   1016. 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   1017. 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   1018. 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   1019. 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   1020. 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   1021. 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   1022. 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   1023. 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   1024. 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   1025. 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   1026. 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   1027. 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   1028. 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   1029. 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   1030. 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   1031. 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   1032. 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   1033. 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   1034. 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   1035. 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   1036. 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   1037. 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   1038. 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   1039. 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   1040. 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   1041.